Preparation of (2-cyanoethyl) ketones

ABSTRACT

A PROCESS FOR THE PREPARATION OF (2-CYANOETHYL) KETONES BY THE HYDROLYSIS OF THE CORRESPONDING (2-CYANOETHYL)-N-SUBSITUTED KETOIMINE WITH THE SUBSEQUENT RECOVERY OF A PRIMARY AMINE, THE PRIMARY AMINE BOILING AT A LOWER TEMPERATURE THAN WATER AND/OR FORMING WITH WATER AN AZEOTROPE BOILING AT A LOWER TEMPERATURE THAN WATER AND CARRYING ON ITS NITROGEN ATOM THE SAME GROUP AS THAT OF THE NITROGEN ATOM OF THE CORRESPONDING KETOIMINE IS DISCLOSED. WHEN THE RESULTING KETONE IS 5-CYANOPENTANONE-2 THIS MAY BE USED AS A STARTING PRODUCT FOR THE PREPARATION OF A-PIPECOLINE.

United States Patent PREPARATION OF (Z-CYANOETHYL) KETONES Siemen H.Green and Johannes J. M. Deumens, Geleen,

Netherlands, assignors to Stamicarbon N.V., Heerlen,

Netherlands N0 Drawing. Filed Sept. 15, 1970, Ser. No. 72,494 Claimspriority, applicati6o91i Nsaherlands, Sept. 26, 1969,

Int. Cl. C07c 121/02, 121/34 US. Cl. 260-465.1 Claims ABSTRACT OF THEDISCLOSURE A process for the preparation of (2-cyanoethyl) ketones bythe hydrolysis of the corresponding (2-cyanoethyl)-N-substitutedketoimine with the subsequent recovery of a primary amine, the primaryamine boiling at a lower temperature than water and/ or forming withwater an azeotrope boiling at a lower temperature than water andcarrying on its nitrogen atom the same group as that of the nitrogenatom of the corresponding ketoimine is disclosed. When the resultingketone is S-cyanopentanone-Z this may be used as a starting product forthe preparation of a-pipecoline.

BACKGROUND OF THE INVENTION The present invention relates to a processfor the preparation of (Z-cyanoethyl) ketones by hydrolysis of thecorresponding (2-cyanoethyl) N substituted ketoimines. -A similarprocess has already been proposed in the US. Pat. 2,768,962. Accordingto this patent, the compound to be hydrolyzed can be prepared fromacrylonitrile and an N-substituted ketoimine, While the N-substitutedketoimine can be synthesized from a primary amine and the subjectketone.

According to the present invention, and with respect to the followingreactions, the hydrolysis of (2cyanoethyl)-N-substituted ketoiminesyields a primary amine in addition to the (2-cyanoethyl) ketone (III).In the resulting primary amine, the nitrogen atom thereof carries thesame substituent as carried by the nitrogen atom in the ketoirnine. 1fthe primary amine is then recovered, it can be reused for thepreparation of the compound to be hydrolyzed (a (Z-cyanoethyl) Nsu'bstithted ketoimine) by causing the primary amine thus recovered toreact with the subject ketone (I) and subsequently converting theresulting, ketoimine with acrylonitrile (II). A (2-cyanoethyl) ketone isthus obtained in an indirect way from acrylonitrile and the ketone inquestion, which is of great significance since in several cases directreaction of acrylonitrile with a ketone often produces un desiredby-products.

The preparation of 3-(2-cyanoethyl)-pentanone-2 according to the presentinvention with cyclohexylamine being used as the primary amine, isexemplified by the following reactions:

3,686,262 Patented Aug. 22, 1972 ice According to the above-mentionedUS. patent, the hydrolysis of (Z-cyanoethyl)-N-substituted ketoimines,as well as the hydrolysis of similar aldimines, can be effected with anacid, for instance with sulphuric acid. However, application of acid inthis hydrolysis has the disadvantage that the resulting hydrolysismixture contains the primary amine not in the free form, but in the formof a salt. The working up of such an acid hydrolysis mixture, and thenobtaining the primary amine in its free form, is a fairly complicatedoperation. In addition, this procedure requires the use of a base, forexample sodium hydroxide, to liberate the amine.

DESCRIPTION OF THE INVENTION It has now been found that in the case of(Z-cyanoethyl) N substituted ketoimines, the hydrolysis reaction canvery suitably be conducted Without an acid, thereby avoiding thedisadvantages thereof, if the starting material is a(2-cyanoethyl)-N-substituted ketoimine of the general formula:

wherein R and R are hydrocarbon radicals of 1-8 carbon atoms and R and Rare hydrogen, hydrocarbon radicals of 1-8 carbon atoms or 2-cyanoethylgroups and wherein R and R together with the two adjacent carbon atomscan form a ring structure of 5, 6 or 7 carbon atoms, which, uponhydrolysis, yields a primary amine of the general formula:

where R is the same group as identified above, the primary amine boilingat a lower temperature than water and/or forming with water an azeotropeboiling at a lower temperature than Water. Suitable starting materialsare disclosed in US. Pat. 2,768,962; however, the preferred method ofpreparation of a mono-(Z-cyanoethyl) acetonimine to be hydrolysedaccording to the present invention is described in application Ser. No.30,597, filed Apr. 21, 1970, the disclosure of which is herebyincorporated by reference. When a ketoimine having the above-mentionedproperties is subjected to distillation conditions in the presence ofwater, the ketoimine can be hydrolyzed almost completely with formationof a distillate containing the primary amine and a residue containingthe (2-cyanoethyl) ketone. Surprisingly, this is neither attended withsteam distillation of the starting compound nor with an undesired sidereaction, such as hydrolysis of a cyano group to acid amide. The(Z-cyanoethyl) ketones thus produced are of the general formula:

R4 RaC( J-OH2CHz-CN where R R and R are as identified above.

The present invention, therefore, provides a process for the preparationof (2-cyan0ethyl) ketones by hydrolysis of the corresponding(Z-cyanoethyl)-N-substituted ketoimines to a primary amine,characterized in that the starting material is a(2-cyanoethyl)-N-substituted ketoimine which upon hydrolysis yields aprimary amine boiling at a lower temperature than water and/or formingan azeotrope with water boiling at a lower temperature than water and inthat the ketoimine starting material is distilled in the presence ofwater to yield a distillate containing the primary amine and a residuecontaining the (2-cyanoethyl) ketone.

In comparison with the acid hydrolysis the process according to thepresent invention has the important advantage that no acid is required,and hence no base either, for liberating the primary amine. In addition,conducting the process is much simpler.

Several substituents attached to the nitrogen atom, as represented by Rabove, of the ketoimine to be hydrolyzed, which meet the requirement ofhydrolyzing with formation of a primary amine which has a lower boilingpoint than water and/or combines with water to yield an azeotrope havinga lower boiling point than water are hydrocarbon radicals having from 1to 8 carbon atoms. Examples of such substituents are methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, n-hexyl,cyclohexyl, isopentyl, l-methylbutyl, l-ethylpropyl and 2- methylbutyl.Preferred substituents are n-propyl, isopropyl, isobutyl, n-butyl,secondary butyl or cyclohexyl. Application of cyclohexyl as asubstituent has the special advantage that the cyclohexylamine to beformed in the hydrolysis reaction is a particularly suitable amine forthe preparation of various (Z-cyanoethyl)-N-substituted ketoimines.

The process according to the invention s preferably carried out underatmospheric pressure. A lower pressure can also be employed, but thelower distillation temperature attendant with it may have an undulylowering effect on the reaction rate. Application of a pressure aboveatmospheric is equally possible, but may have the drawback that thehigher distillation temperature will give rise to undesired sidereactions.

The process of the present invention is conducted at a temperature notin excess of the temperature corresponding to the boiling conditions ofthe water at the pressure employed. When the reaction is carried out atatmospheric pressure this means a reaction temperature not in excess ofabout 100 C.

In the process according to the present invention, one molecule of waterper molecule of the compound to be hydrolyzed is required for thehydrolysis reaction. Further, the amount of water is needed whichdistils over with the primary amine. Hence, the more water distils overwith the primary amine, the larger the quantity of water to be supplied.Normally, a very good result can be obtained with 1 20 molecules ofWater per 1 molecule of the compound to be hydrolyzed. The ketonesproduced according to the present invention enjoy several uses. Forexample, when the resulting ketone is 5-cyanopentanone-2 (also known asS-oxocapronitrile), the product can be used as the starting material forthe preparation of ozpipecoline, as described in the Journal of theAmerican Chemical Society, 72, 1950, page 2594, the disclosure of whichis hereby incorporated by reference. Uses for the primary aminerecovered have been stated above.

The process according to the present invention will be furtherelucidated in the following non-limiting examples. All of the followingexamples were conducted at atmospheric pressure unless other pressuresare stated:

Example I In a flask of 100 milliliters capacity, provided with adistillation column, 16.6 grams of N-butyl-S-cyanopentanone- 2-imine(100 millimoles) was heated together with grams of water. At about 78 C.butylamine starts distilling over. The distillation was continued untilpure water began to distill. Titrimetric and mass-spectrometric analysisshowed that the aqueous distillate contained 7 grams of butylamine (96millimoles). The homogeneous distillation residue left in the flask wasextracted with ether. After the resulting solution had been dried, theether Was removed and the residue distilled at reduced pressure of 4 0.7mm. Hg. This yielded 10.3 grams of S-cyanopentanon- 2 (93 millimoles,boiling point 63 C. at 0.7 mm. mercury, 11 1.4300). The yields ofS-cyanopentanone-Z and butylamine are 93% and 96%, respectively.

Example II In a flask of 100 milliliters capacity, provided with adistillation column, 20.6 grams of a mixture consisting of about byWeight of N-cyclohexyl-5-cyano-3-rnethylpentanone-Z-imine and about 10%by weight of N-cyclohexyl-6-cyanohexanone-3-imine (100 millimoles inall) was heated together with 35 grams of water. A mixture ofcyclohexylamine and water distilled over and heating was continued untilpure water began to distill. Massspectrometric analysis showed that theaqueous distillate contained 9.5 grams of cyclohexylamine whichcorresponded to a yield of 96%, calculated on the quantity of startingimine.

The liquid left in the column was then extracted with ether. Afterdrying, and removal of the ether by means of distillation, 12.3 g. ofresidue remained. Mass-spectrometric analysis showed that this residueconsisted of 90% by weight of 5-cyano-3-methylpentanone-2 and of 7% byweight of 6-cyanoheXanone-3. Calculated on the quantity of originalimine, the total yield of the two cyanoketones equalled Example IH In aflask of 250 milliliters capacity, provided with a distillation column,384 grams of N-cyclohexyl-5-cyanopentanone-Z-imine (200 millimoles) washeated with 36 grams of water. During the reaction, a mixture ofcyclohexylamine and water distilled over and was recovered. Heating wascontinued until pure water began to distill. The distillate contained19.2 grams of cyclohexylamine (194 millimoles), which corresponded to ayield of 97%. The liquid left in the flask was distilled at reducedpressure. A total of 21 grams of 5-cyanopentanone-2 (189 millimoles) wasobtained, which corresponded to a yield of 94.5%.

Example IV In a flask of 250 milliliters capacity, provided with a feedtube and a splash bulb with cooler, 38.4 grams of N-cyclohexyl-S-cyanopentanone-2-imine was heated to 100 C. Subsequently,steam was passed into the liquid via the feed tube. A mixture of waterand cyclohexylamine distilled over and was recovered. The introductionof steam was continued until pure water began to distill. The productwas 19.1 grams of cyclohexylamine (representing a yield of 96.5% Theaqueous liquid left in the flask was distilled at reduced pressure toremove the water. A total of 20.9 grams of S-cyanopentanone was thusobtained, representing a yield of 94%.

,Example V In a flask of 100 milliliters capacity, provided with adistillation column, 24.5 grams of N-cyclohexyl-3-(2-cyanoethyl) 5cyanopentanone-Z-imine (100 millimoles) and 25 grams of water weresubjected to distillation. The distillation was continued until purewater began to distill. The distillate contained 9.8 grams ofcyclohexylamine (yield 99%). After the water left in the flask had beenremoved by distillation at reduced pressure of about 15 mm. Hg, thereremained 16.5 grams of residue which, as appeared from proton resonancespectrometric analysis, consisted almost completely of3-(2-cyanoethyl)-5-cyanopentanone-Z. Distillation of the residue atreduced pressure yielded 15.4 grams of3-(Z-cyanoethyl)-5-cyanopentanone- 2 (94 millimoles, boiling point C. at0.2mm. mercury pressure, 11 1.4360), which corresponded to a yield of94%.

Example VI In a flask of 50 milliliters capacity, provided with adistillation column, 16.6 grams of a mixture consisting of about 90% byweight of N-isopropyl-S-cyano-3-methylpentanone-2-imine and of about 10%by weight of N- isopropyl-6-cyan0hexanone-3-imine (100 millimoles inall), was heated together with 3.6 grams of water. At a temperaturebet-ween 31 and 35 C. isopropylamine distilled over, which was collectedin a flask cooled to C. The product was 5.6 grams of isopropylamine(yield 95% The distillation residue was freed of water by distillationat reduced pressure of about 15 mm. Hg. The product was 12.2 grams ofliquid, which as appeared from proton resonance spectrometric analysis,consisted of 88% by weight of S-cyano-3-methylpentanone-2 and of 12% byweight of 6-cyanohexanone-3 (98 millimoles in all). Calculated on thetotal quantity of starting product the total yield of cyanoketone was98% What is claimed is:

1. Process for the hydrolysis of a (2-cyanoethyl)-N- substitutedketoimine of the general formula:

wherein R is an alkyl or cycloalkyl radical of 1-8 carbon atoms and R isan alkyl radical of l-8 carbon atoms, R and R are hydrogen, alkylradicals of 1-8 carbon atoms or 2-cyanoethyl groups and R and R togetherwith the two adjacent carbon atoms can form 5-, 6- or 7-memberedcarbocyclic ring, reacting said ketoimine with water in an amount of atleast equimolecular to said ketoimine, at a temperature not in excess ofthe boiling temperature of the water at the pressure employed, to formthe corresponding (Z-cyanoethyl) ketone of the general formula:

wherein R R and R are as identified above, and a primary amine of theformula:

wherein R is as identified above, wherein said ketoimine of Formula I issubjected to distillation conditions in the presence of water withformation of a distillate containing said primary amine of Formula IIIin its free form, and a residue containing the (Z-cyanoethyl) ketone ofFormula II.

2. Process as claimed in claim 1 wherein said R group is selected fromthe class consisting of cyclohexyl, n-propyl, isopropyl, n-butyl,isobutyl and secondary butyl.

3. Process as claimed in claim 1 wherein from 1 to 20 moles of water areused per mole of the compound of Formula I to be hydrolyzed.

4. Process as claimed in claim 1 wherein said (2-cyanoethyl) ketone isselected from the class consisting of S-cyanopentanone-Z,S-cyano-3-methylpentanone-2-, 6-cyanohexanone-El, and 3 (2 cyanoethyl) 5cyanopentanone-2.

5. Process for the hydrolysis of a (2-cyanoethyl)-N- substitutedketoimine of the formula:

R; wherein R is an alkyl or cycloalkyl group of l-6 carbon atoms, R ismethyl or ethyl, R and R are hydrogen, methyl or cyanoethyl, saidprocess including:

reacting said ketoimine with water in an amount of at leastequimolecular to said ketoimine, at a temperature not in excess of theboiling temperature of the water at the reaction pressure employed, toform the corresponding (2-cyanoethyl) ketone of the formula:

R wherein R R and R are as identified above, and a primary amine of theformula:

(III) References Cited UNITED STATES PATENTS 2,768,962 10/1956 Krimm260-465.8X

JOSEPH PAUL BRUST, Primary Examiner US. Cl. X.R.

260-464, 465.5 R, 465.8 R, 563 R, 563 c, 566 R, 583 R, 583 J p

